Compounds and compositions useful for producing analgesia

ABSTRACT

Alkadienamide compounds, and pharmaceutically-acceptable salts thereof, of the formula: ##STR1## wherein X is O or S; R is straight or branched diene having from 11 to 23 carbon atoms; R 1  is H, OH, or OCH 3  ; R 2  is OH or a short-chain ester; and wherein at least one of R 1  and R 2  is OH or OCH 3 . Compositions, useful for producing analgesia in humans or lower animals, comprise a safe and effective amount of: an alkadienamide, pharmaceutically-acceptable salts thereof, or mixtures thereof; and a pharmaceutically-acceptable carrier. Preferably, these alkadienamides are N-vanillyl-alkadienamides. Methods of treatment, comprising administering a safe and effective amount of these alkadienamides, pharmaceutically-acceptable salts thereof, or mixtures thereof, include methods of parenteral, oral, and topical administration.

BACKGROUND OF THE INVENTION

This invention relates to compositions, containing certainN-phenylmethylalkenamides, having analgesic activity.

While "pain" is incapable of precise definition due to its basicallysubjective nature, it can generally be said that the term refers tofeelings of distress or suffering caused by stimulation of specializednerve endings. A great variety of drugs have been developed to reducepain in man and other animals; some directed to eliminating pain at itssource, and others directed to blocking the assimilation of pain by thebrain. Among the latter group of drugs that are designed to block thesensation of pain, are the analgesics, which generally relieve painwithout causing unconsciousness. Analgesics can be further classified intwo main categories: opioid analgesics, including morphine, codeine,levorphanol, and the morphine-like analgesics meperidine, and methadone;and antipyretic analgesics, such as aspirin, phenacetin, acetaminophen,phenylbutazone, and indomethacin.

Although the precise pharmacological action of these analgesics isuncertain, there are certain effects which readily distinguish theopioid analgesics from the antipyretics. In particular, the antipyreticsare weak analgesics, with much of their effect in the peripheral nervoussystem, so that behavioral changes do not usually occur. Generally,these analgesics relieve only somatic pain originating from muscles,joints, tendons and fasciae, and are ineffective against deep visceralpain. However, the opioid analgesics are quite effective against alltypes of pain, with broad based action in the central nervous system.Aside from potent analgesia, the opioids, also known as narcotics, oftenproduce effects on mood and other behavioral changes. Perhaps the mostnotable side effect of the opioid analgesics is the fact that theirrepeated use is associated with tolerance as well as psychic andphysical dependence.

It has been recently discovered that capsaicin, a natural product ofcertain species of the genus Capsicum, induces analgesia in animals.Capsaicin (8-methyl-N-vanillyl-6E-nonenamide) and "synthetic" capsaicin(N-vanillylnonanamide) are disclosed as analgesics in U.S. Pat. No.4,313,958, LaHann, issued Feb. 2, 1982. Analgesic activity of capsaicinhas also been discussed in the chemical and medical literature,including Yaksh, et al., Science, 206, 481-483 (1979). The use ofcapsaicin to prevent dipilatory irritation is also disclosed in U.S.patent application Ser. No. 330,731, LaHann, et al., filed Dec. 14,1981.

Specifically, capsaicin prevents the development of cutaneoushyperalgesia and also provides relief of deep visceral pain and severepain. In certain tests, capsaicin produces a level of analgesiacomparable to morphine, yet it is not antagonized by such narcoticantagonists as nalorphine and naloxone. Thus, capsaicin does not appearto belong to either of the major categories of analgesics, describedabove.

Compounds structurally similar to capsaicin have been described in thechemical literature. These references, though, do not suggest analgesicactivity for these compounds. For example, Newman, "Natural andSynthetic Pepper-Flavored Substances (6)," Chemical Products, 102-106(1954) lists the relative pungency of approximately 164 compounds,including N-vanillyloleamide and other alkenamide derivatives ofcapsaicin. Ott and Zimmermann, Liebigs Ann., 425, 314-337 (1921)discloses a synthesis for N-vanillyloleamide. A synthesis forN-vanillyllinoleamide is disclosed in Ferris, Australian Commonwealth,Dep. Supply, Def. Stand. Lab., No. 89 (1966) (Chem. Abs. 67:22919).

U.S. Pat. No. 4,238,505, Nelson, issued Dec. 9, 1980, discloses3-hydroxyacetanilide for use in producing analgesia in animals. U.S.patent application Ser. No. 359,464, LaHann, et al., filed Mar. 18, 1982now U.S. Pat. No. 4,424,206, issued Jan. 3, 1984, describeshydroxyphenylacetamides with analgesic and anti-irritant activity.Similarly, analgesic and anti-irritant activity is disclosed forN-vanillylsulfonamides in U.S. patent application Ser. No. 360,953,Buckwalter, et al., filed Mar. 23, 1982 now U.S. Pat. No. 4,401,663,issued Aug. 30, 1983; N-vanillylureas in U.S. patent application Ser.No. 381,672, Buckwalter, et al., filed May 25, 1982 now U.S. Pat. No.4,460,602, issued July 17, 1984; and N-vanillylcarbamates in U.S. patentapplication Ser. No. 384,685, Buckwalter, et al., filed June 3, 1982 nowU.S. Pat. No. 4,443,473, issued Apr. 17, 1984.

It has now been discovered that certain N-phenylmethyl alkadienamideshave analgesic activity in humans and lower animals. In particular,these alkenamides have potent analgesic activity similar to that ofcapsaicin, but are substantially less toxic.

SUMMARY OF THE INVENTION

The present invention provides compounds useful for producing analgesiain humans and lower animals, of the formula: ##STR2## wherein X is O orS, R is straight or branched diene having from 11 to 23 carbon atoms, R₁is H, OH, or OCH₃, R₂ is OH or a short-chain ester, wherein at least oneof R₁ and R₂ is OH or OCH₃ ; and pharmaceutically-acceptable saltsthereof.

This invention also provides compositions comprising a safe andeffective amount of these compounds, or mixtures thereof, and apharmaceutically-acceptable carrier. Also provided are methods forproducing analgesia by administering the compounds and compositions ofthis invention.

DESCRIPTION OF THE INVENTION

The compositions and methods of this invention incorporate certainN-[(substituted phenyl)methyl]-diunsaturated amides (e.g.,N-vanillyl-diunsaturated amides), or pharmaceutically-acceptable saltsthereof, (herein "alkadienamides") of the formula: ##STR3## wherein X isO or S; R is straight or branched diene having from 11 to 23 carbonatoms; R₁ is H, OH or OCH₃ ; R₂ is OH or a short-chain ester; andwherein at least one of R₁ and R₂ is OH or OCH₃. R preferably containsfrom 16 to 21 carbon atoms and, preferably, unsaturated bonds are atposition six or greater, i.e., wherein R is a (m,n-alkadiene), m is atleast six. Also preferred are alkadienamides wherein X is O,alkadienamides wherein R₁ is OCH₃ and R₂ is OH, and alkadienamideswherein R₂ is a short-chain (i.e., C₁ -C₆) ester, e.g., acetoxy.

Preferred alkadienamides include those where R is derived from suchdiunsaturated fatty acids as (Z,Z)-9,12-octadecadienoic (linoleic) acid,(E,E)-9-12-octadecadienoic (linoelaidic) acid,(Z,E)-9-12-octadecadienoic acid, (Z,E)-9,11-octadecadienoic acid,(E,E)-10,13-nonadecadienoic acid, and (E,E)-11,14-eicosadienoic acid.Preferred pharmaceutically-acceptable alkadienamide salts include thesodium, potassium, calcium, magnesium, and ammonium salts.

The alkadienamides described herein can be readily prepared by thefollowing general synthetic scheme: ##STR4## The fatty acids used in thesynthesis of preferred alkadienamides are commercially-available.

Compositions

The compositions of the present invention comprise:

(a) a safe and effective amount of an alkadienamide; and

(b) a pharmaceutically-acceptable carrier.

A safe and effective amount of alkadienamide is that amount whichprovides analgesia, thereby alleviating or preventing the pain beingtreated at a reasonable benefit/risk ratio, as is intended with anymedical treatment. Obviously, the amount of alkadienamide will vary withsuch factors as the particular condition that is being treated, theseverity of the condition, the duration of the treatment, the physicalcondition of the patient, the nature of concurrent therapy (if any), thespecific formulation and carrier employed, and the solubility andconcentration of alkadienamide therein.

Depending upon the particular route of administration, a variety ofpharmaceutically-acceptable carriers, well known in the art, may beused. These include solid or liquid fillers, diluents, hydrotropes,surface-active agents, and encapsulating substances. The amount of thecarrier employed in conjunction with the alkadienamide is sufficient toprovide a practical quantity of material per unit dose of analgesic.

Pharmaceutically-acceptable carriers for systemic administration, thatmay be incorporated into the compositions of this invention, includesugars, starches, cellulose and its derivatives, malt, gelatin, talc,calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid,phosphate buffer solutions, emulsifiers, isotonic saline, andpyrogen-free water. Specific pharmaceutically-acceptable carriers aredescribed in the following U.S. patent applications, all incorporated byreference herein: Ser. No. 359,464, LaHann, et al., filed Mar. 18, 1982now U.S. Pat. No. 4,424,206, issued Jan. 3, 1984; Ser. No. 360,953,Buckwalter, et al., filed Mar. 23, 1982 now U.S. Pat. No. 4,401,663,issued Aug. 30, 1983; Ser. No. 381,672, Buckwalter, et al., filed May25, 1982 now U.S. Pat. No. 4,460,602, issued July 17, 1984; and Ser. No.384,685, Buckwalter, et al., filed June 3, 1982 now U.S. Pat. No.4,443,473, issued Apr. 17, 1984. Preferred carriers for parenteraladministration include propylene glycol, ethyl oleate, pyrrolidone,ethanol, and sesame oil. Preferably, the pharmaceutically-acceptablecarrier, in compositions for parenteral administration, comprises atleast about 90% by weight of the total composition.

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. These oral forms comprisea safe and effective amount, usually at least about 5%, and preferablyfrom about 25% to about 50% of the alkadienamide. Tablets can becompressed, tablet triturates, enteric-coated, sugar-coated, film-coatedor multiple compressed, containing suitable binders, lubricants,diluents, disintegrating agents, coloring agents, flavoring agents,flow-inducing agents, and melting agents. Liquid oral dosage formsinclude aqueous solutions, emulsions, suspensions, solutions and/orsuspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules,containing suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, melting agents, coloring, andflavoring agents. Preferred carriers for oral administration includegelatin, propylene glycol, cottonseed oil and sesame oil. Specificexamples of pharmaceutically-acceptable carriers and excipients that maybe used to formulate oral dosage forms, which may be used in formulatingoral dosage forms containing alkadienamides, are described in U.S. Pat.No. 3,903,297, Robert, issued Sept. 2, 1975, incorporated by referenceherein. Techniques and compositions for making solid oral dosage formsare described in Marshall, "Solid Oral Dosage Forms," ModernPharmaceutics, Vol. 7, (Banker and Rhodes, editors), 359-427 (1979),incorporated by reference herein.

The compositions of the present invention can also be administeredtopically to a biologic subject, i.e., by the direct laying on orspreading of the composition on epidermal or epithelial tissue. Suchcompositions include lotions, creams, solutions, gels and solids. Thesetopical compositions comprise a safe and effective amount, usually atleast about 0.5%, and preferably from about 1% to about 2%, of thealkadienamide. Suitable carriers for topical administration of thealkadienamide preferably remain in place on the skin as a continuousfilm and resist being washed off easily by perspiration or by immersionin water. Generally, the carrier is organic in nature and capable ofhaving dispersed or dissolved therein the alkadienamide. The carrier mayinclude pharmaceutically-acceptable emollients, emulsifiers, thickeningagents, and solvents.

Specific systemic and topical formulations useful in this invention aredescribed in the following U.S. patent applications, all incorporated byreference herein: Ser. No. 359,464, LaHann, et al., filed Mar. 18, 1982now U.S. Pat. No. 4,424,206; issued Jan. 3, 1984; Ser. No. 360,953,Buckwalter, et al., filed Mar. 23, 1982 now U.S. Pat. No. 4,401,663,issued Aug. 30, 1983; Ser. No. 381,672, Buckwalter, et al., filed May25, 1982 now U.S. Pat. No. 4,460,602, issued July 17, 1984; and Ser. No.384,685, Buckwalter, et al., filed June 3, 1982 now U.S. Pat. No.4,443,473, issued Apr. 17, 1984. Topical vehicles, useful herein, aredisclosed in the following U.S. patent applications, incorporated byreference herein: "Improved Penetrating Topical PharmaceuticalCompositions Containing 1-dodecylazacycloheptan-2-one", Ser. No.560,275, Cooper, filed June 21, 1983; and "Penetrating TopicalPharmaceutical Compositions Containing N-(2-hydroxyethyl)-pyrrolidone",Ser. No. 506,273, Cooper, filed June 21, 1983. Additional formulations,useful for parenteral, oral, and topical administration ofalkadienamides, are disclosed in the following U.S. patent applicationsconcurrently filed herewith, all incorporated by reference herein:"Compositions Useful for Producing Analgesia", Ser. No. 514,206, filedJuly 14, 1983, LaHann and Buckwalter; "Novel Compounds and CompositionsUseful for Producing Analgesia", Ser. No. 514,204, filed July 14, 1983,Janusz and LaHann; and "Novel Compounds and Compositions Useful forProducing Analgesia", Ser. No. 514,205, filed July 14, 1983, Janusz,Buckwalter and LaHann.

METHODS FOR PRODUCING ANALGESIA

The present invention also encompasses methods of producing analgesia inhumans or lower animals through administering, to the human or loweranimal, a safe and effective amount, usually from about 1 mg to about3600 mg per day, preferably from about 200 mg to about 2000 mg per day,of an alkadienamide. While dosages higher than the foregoing areeffective to produce analgesia, care must be taken in some individualsto prevent adverse side effects. The alkadienamides and compositions ofthis invention can be used to treat and prevent pain, and to provideanalgesia in various disorders at the deeper structures, muscles,tendons, bursa and joints associated with disease and trauma, and invarious other conditions in which compounds such as aspirin, codeine,and morphine have heretofore been used to alleviate pain and discomfort.

The alkadienamides and compositions of the instant invention can beadministered topically or systemically. Systemic application includesany method of introducing the alkadienamide into the tissues of thebody, e.g., intrathecal, epidural, intramuscular, transdermal,intravenous, intraperitoneal, subcutaneous, sublingual, and oraladministration.

A preferred method of parenteral administration is through intramuscularinjection. As is known and practiced in the art, all formulations forparenteral administration must be sterile. For mammals, especiallyhumans, (assuming an approximate body weight of 70 kg) individual dosesof from about 2 mg to about 400 mg of alkadienamide are acceptable.Individual doses of from about 50 mg to about 200 mg are preferred.

A preferred method of systemic application of the alkadienamides isthrough oral administration. For mammals, especially humans, (assumingan approximate body weight of 70 kg) individual doses of from about 1 mgto about 900 mg of alkadienamide are acceptable. Individual doses offrom about 50 mg to about 600 mg are especially preferred.

Topical administration can be used to produce local or systemicanalgesia, through directly laying on or spreading a safe and effectiveamount of the alkadienamide, or composition containing an alkadienamide,on epidermal or epithelial tissue, including outer skin and oral,gingival, and nasal tissue. The amount of alkadienamide to be topicallyadministered depends upon such factors as the sensitivity, type andlocation of tissue to be treated, the composition and carrier (if any)to be administered, and the particular alkadienamide to be administeredas well as the particular disorder to be treated and the extent to whichsystemic (as distinguished from local) analgesic effects are desired.The extent of systemic analgesia also depends upon such factors as theamount of alkadienamide, the area of tissue to be covered, and theability of the alkadienamide composition to penetrate the skin tissues.

The following non-limiting Examples illustrate the compositions,processes, and uses of the present invention.

EXAMPLE I

N-vanillyl-(E,E)-9,12-octadecadienamide was synthesized by the followingmethod: ##STR5## Specifically 6.88 g of4-hydroxy-3-methoxybenzylamine-HCl was dissolved in 50 ml oftetrahydrofuran (THF), and stirred. Added were 14 ml of a 5N solution ofNaOH, and the mixture was stirred for 10 to 15 minutes. Then 10.6 g of(E,E)-9,12 octadecadienoyl chloride (linoelaidoyl chloride), dissolvedin THF, was added dropwise. The mixture was then stirred overnight,allowing it to come to room temperature. The solvent was evaporated andthe residue partitioned between ethyl ether and water. The organic phaseextract was washed with HCl, sodium bicarbonate, water, and brine, andthen dried and filtered. 16 g of crudeN-vanillyl-(E,E)-9,12)-octadecadienamide was obtained. Purification byrecrystallization from ether and pentane gave 9.4 g of analytically pureproduct. Its structure was confirmed via nuclear magnetic resonance andinfrared spectroscopy.

In the above example, (Z,Z)-9,12-octadecadienoyl chloride,(Z,E)-9,12-octadecadienoyl chloride, (Z,E)-9,11-octadecadienoylchloride, (E,E)-10,13-nonadecadienoyl chloride, and(E,E)-11,14-cosadienoyl chloride are substituted, respectively, for(E,E)-9,12-octadecadienoyl chloride, thereby obtaining each respective Nvanillyl-alkadienamide.

EXAMPLE II

An analgesic composition, according to the present invention, was madecomprising:

    ______________________________________                                        N--vanillyl-(E,E)-9,12-octadecadienamide                                                              127.2    mg                                           ethanol                 0.75     ml                                           pyrrolidone             0.75     ml                                           ______________________________________                                    

The composition was made by simple dissolution of the alkadienamide inthe liquid solvents. A mouse weighing 30 g, was injected subcutaneouslywith 0.1 ml of the composition, producing analgesia.

EXAMPLE III

A composition, according to the instant invention, for parenteraladministration, is made with the following ingredients:

    ______________________________________                                        N--vanillyl-(E,E)-9,12-octadecadien-                                                              100 mg/ml of carrier                                      amide                                                                         carrier (percent-by-weight):                                                  propylene glycol    72%                                                       polyethylene glycol 17%                                                       water               10%                                                       benzyl alcohol       1%                                                       ______________________________________                                    

The alkadienamide is dissolved in the carrier and a human subject,weighing 70 kg, is injected subcutaneously with 1.0 ml of thecomposition thereby prepared, producing analgesia. At eight-hourintervals, two more subcutaneous injections are made, of 1.0 ml of thecomposition per administration, for a total of 300 mgN-vanillyl-(E,E)-9,12-octadecadienamide administered over atwenty-four-hour period.

In the above example, N-vanillyl-(Z,Z)-9,12-octadecadienamide,N-vanillyl-(Z,E)-9,12-octadecadienamide,N-vanillyl-(Z,E)-9,11-octadecadienamide,N-vanillyl-(E,E)-10,13-nonadecadienamide,N-vanillyl-(Z,Z)-11,14-eicosadienamide, andN-vanillyl-(E,E)-11,14-eicosadienamide are substituted, respectively,for N-vanillyl-(E,E)-9,12-octadecadienamide, with substantially similarresults.

EXAMPLE IV

A composition, according to the instant invention, for parenteraladministration, is made with the following components:

    ______________________________________                                        N--vanillyl-(E,E)-9,12-octadecadien-                                                              100 mg/ml of carrier                                      amide                                                                         carrier (percent-by-weight):                                                  sesame oil          98%                                                       benzyl alcohol       2%                                                       ______________________________________                                    

A human subject, weighing 70 kg, is injected via deep-intramuscularinjection, with 1.0 ml of the composition prepared above, producinganalgesia.

In the above example, N-vanillyl-(Z,Z)-9,12-eicosadienamide,15-hydroxy-N-vanillyl-(Z,Z)-9,12-octadecadienamide,N-vanillyl-(E,E)-9,12-octadecadienethioamide, andN-[(3,4-dihydroxyphenyl)methyl]-(E,E)-9,12-octadecadienamide and aresubstituted, respectively, for N-vanillyl-(E,E)-9,12-octadecadienamide,with substantially similar results.

EXAMPLE V

A composition, according to the instant invention, for parenteraladministration, is made with the following components:

    ______________________________________                                        N--vanillyl-(Z,Z)-9,12-octadeca-                                                                  100 mg/ml of carrier                                      dienamide                                                                     carrier: sodium citrate buffer                                                with (percent-by-total weight):                                               lecithin            0.48%                                                     carboxymethylcellulose                                                                            0.53%                                                     povidone            0.50%                                                     methyl paraben      0.11%                                                     propyl paraben       0.011%                                                   ______________________________________                                    

The above ingredients are admixed, forming a suspension. A humansubject, weighing approximately 70 kg, is injected, via intramuscularinjection, with 2.0 ml of the composition formed above, producinganalgesia.

EXAMPLE VI

A composition, according to the instant invention, for parenteraladministration, is made by admixing the following components:

    ______________________________________                                        N--[(4-acetoxy-3-methoxyphenyl)-                                                                  100 mg/ml of carrier                                      methyl]-(E,E)-9,12-octadecadienamide                                          carrier (percent by weight):                                                  ethyl oleate        98.0%                                                     benzyl alcohol       2.0%                                                     ______________________________________                                    

A human subject, weighing 70 kg, is injected via intramuscularinjection, with 2.0 ml of the composition prepared above, producinganalgesia.

In the above example,N-[(4-butoxy-3-methoxyphenyl)methyl]-(E,E)-9,12-octadecadienamide issubstituted forN-[(4-acetoxy-3-methoxyphenyl)methyl]-(E,E)-9,12-octadecadienamide, withsubstantially similar results.

EXAMPLE VII

A composition, according to the instant invention, is made with thefollowing components:

    ______________________________________                                        N--vanillyl-(E,E)-9,12-octadeca-                                                                       2000   mg                                            dienamide                                                                     sesame oil               50     ml                                            benzyl alcohol           6      ml                                            8% gelatin in water      100    ml                                            tartaric acid            60     mg                                            ______________________________________                                    

The alkadienamide is dissolved in the sesame oil and benzyl alcohol. Anemulsion is obtained through adding this solution to a mixture of thegelatin and tartaric acid. This emulsion is administered orally to ahuman subject, weighing approximately 70 Kg, producing analgesia.

EXAMPLE VIII

A composition, according to the instant invention, for oraladministration, is made with the following components:

    ______________________________________                                        N--vanillyl-(E,E)-10,13-nonadeca-                                                                100 mg/ml of carrier                                       dienamide                                                                     carrier (percent-by-weight):                                                  propylene glycol   100%                                                       ______________________________________                                    

5.0 ml of the syrup thereby prepared is administered orally to a humansubject, producing analgesia.

In the above example, flavoring agents, sweetening agents such assucrose, lactose, mannitol and saccharin, and preservatives such asglycerin, methyl paraben, propylparaben, benzoic acid, sodium benzoateand alcohol, are added, singly or in combination, to the compositionformed above, with substantially similar results.

EXAMPLE IX

A composition, according to the instant invention, for oraladministration, is made with the following components:

    ______________________________________                                        N--vanillyl-(Z,Z)-11,14-eicosadien-                                                              100 mg/ml of carrier                                       amide                                                                         carrier (percent by weight):                                                  cottonseed oil     99%                                                        benzyl alcohol      1%                                                        ______________________________________                                    

Soft gelatin capsules, each having a volume of 0.3 ml, are filled withthe composition formed above. Two capsules are administered to a humansubject every eight hours, producing sustained analgesic effects.

EXAMPLE X

A composition, according to the instant invention, for oraladministration, is made with the following components:

    ______________________________________                                        Component         Bulk    Individual Tablet                                   ______________________________________                                        N--vanillyl-(E,E)-9,12-octa-                                                                    70    g     350     mg                                      decadienamide                                                                 starch            6           30                                              magnesium stearate                                                                              1           5                                               microcrystalline cellulose                                                                      20          100                                             colloidal silicon dioxide                                                                       0.5         2.5                                             povidone          2.5         12.5                                            ______________________________________                                    

The above ingredients are admixed into a bulk mixture, totalling 100 g.Compressed tablets are formed, using tabletting methods known in theart, each containing 0.5 g of the bulk mixture. A human subject,weighing approximately 70 kg, is orally administered two of the tablets,for a total dose of 700 mg of alkadienamide, producing analgesia.

EXAMPLE XI

A composition, according to the instant invention, for oraladministration, is made with the following components:

    ______________________________________                                        Component        Bulk      Individual Tablet                                  ______________________________________                                        N--vanillyl-(Z,Z)-9,12-octa-                                                                   100    g     500     mg                                      decadienamide                                                                 mannitol         97.2         486                                             acacia           5.86         29.3                                            starch           9.62         48.1                                            talc             3.2          16.0                                            calcium stearate 0.42         2.1                                             orange flavor mix                                                                              1.06         5.3                                             ______________________________________                                    

The above ingredients are admixed into a bulk mixture totalling 217.4 g.Chewable tablets are formed, using tabletting methods known in the art,each containing 1.09 g of the bulk mixture, for a total of 200 tabletsformed. A human subject, weighing approximately 70 kg, is orallyadministered three of the tablets, for a total dose of 1500 mg ofalkadienamide, producing analgesia.

EXAMPLE XII

A composition, according to the instant invention, for oraladministration, is made with the following components:

    ______________________________________                                        N--vanillyl-(E,E)-9,12-octadecadienamide                                                                1000   mg                                           starch                    10.2                                                magnesium stearate        5.1                                                 ______________________________________                                    

A capsule is made by filling with the above ingredients, andadministered to a human subject, weighing approximately 70 kg, producinganalgesia.

EXAMPLE XIII

A lotion composition, according to the instant invention, for topicaladministration, is formed through admixing the following components(percentages-by-weight):

    ______________________________________                                        N--vanillyl-(E,E)-11,14-eicosadienamide                                                               2.0%                                                  isopropyl myristate     8.0%                                                  corn oil                5.0%                                                  propylene glycol        5.0%                                                  triethanolamine oleate  5.0%                                                  xanthan gum             0.5%                                                  water                   74.5%                                                 ______________________________________                                    

Approximately 4 ml of the lotion formed is applied to a 80 cm² portionof the skin of a human subject, producing analgesia.

In the above example, 15-methyl-N-vanillyl-(Z,Z)-9,12-octadecadienamideand 15-ethyl-N-vanillyl-(Z,Z)-9,12-octadecadienamide are substituted forN-vanillyl-(E,E)-11,14-eicosadienamide respectively, with substantiallysimilar results.

EXAMPLE XIV

An ointment composition, according to the instant invention, for topicaladministration, is formed with the following components(percentages-by-weight):

    ______________________________________                                        N--vanillyl-(E,E)-9,12-octadeca-                                                                    2.0%                                                    dienamide                                                                     oleyl alcohol         30.0%                                                   cetyl alcohol         40.0%                                                   propylene glycol      28.0%                                                   ______________________________________                                    

The components are admixed and approximately 6 ml of the ointment isapplied to a 100 cm² portion of the skin of a human subject, producinganalgesia.

What is claimed is:
 1. Alkadienamide compounds, andpharmaceutically-acceptable salts thereof, of the formula: ##STR6##wherein X is 0 or S; R is straight or branched diene having from 11 to23 carbon atoms, the stereochemistry of said diene being ZE, EZ, or EE;R₁ is H, OH, or OCH₃ ; R₂ is OH or a short-chain ester; and wherein atleast one of R₁ and R₂ is OH or OCH₃.
 2. Alkadienamide compounds, andpharmaceutically-acceptable salts thereof, according to claim 1, whereinR₁ is OCH₃ and R₂ is OH.
 3. Alkadienamide compounds, andpharmaceutically-acceptable salts thereof, according to claim 1, whereinR₂ is a shortchain ester.
 4. Alkadienamide compounds, andpharmaceutically-acceptable salts thereof, according to claim 2,selected from the group consisting ofN-vanillyl-(Z,E)-9,12-octadecadienamide,N-vanillyl-(E,E)-9,12-octadecadienamide,N-vanillyl-(Z,E)-9,11-octadecadienamide,N-vanillyl-(E,E)-10,13-nonadecadienamide, andN-vanillyl-(E,E-11,14-eicosadienamide.
 5. The alkadienamide compound andpharmaceutically-acceptable salts thereof, according to claim 3, whereinsaid alkadienamide isN-[(4-acetoxy-3-methoxyphenyl)methyl]-(E,E)-9,12-octadecadienamide. 6.The alkadienamide compound N-vanillyl-(Z,Z)-11,14-eicosadienamide, andpharmaceutically-acceptable salts thereof.
 7. A composition forproducing analgesia in humans or lower animals, comprising:(a) a safeand effective amount of an alkadienamide compound orpharmaceutically-acceptable salt thereof, or mixtures thereof, of theformula: ##STR7## wherein X is 0 or S, R is straight or branched dienehaving from 11 to 23 carbon atoms, R₁ is H, OH, or OCH₃, R₂ is OH or ashort-chain ester, and wherein at least one of R₁ and R₂ is OH or OCH₃ ;and (b) a pharmaceutically-acceptable carrier.
 8. A composition,according to claim 7, wherein R is straight or branched diene havingfrom 16 to 21 carbon atoms.
 9. A composition, according to claim 7,wherein R₁ is OCH₃ and R₂ is OH.
 10. A composition, according to claim7, wherein R₂ is a shortchain ester.
 11. A composition, according toclaim 7, comprising a pharmaceutically-acceptable salt of saidalkadienamide compound, selected from the group consisting of sodium,potassium, calcium, magnesium, and ammonium salts.
 12. A composition,according to claim 8, for parenteral administration, comprising at leastabout 90%, by weight, of said pharmaceutically-acceptable carrier.
 13. Acomposition, according to claim 8, for oral administration, comprisingfrom about 25% to about 50%, by weight, of said alkadienamide.
 14. Acomposition, according to claim 9, wherein said alkadienamide compoundis selected from the group consisting ofN-vanillyl-(Z,Z)-9,12-octadecadienamide,N-vanillyl-(Z,E)-9,12-octadecadienamide,N-vanillyl-(E,E)-9,12-octadecadienamide,N-vanillyl-(Z,E)-9,11-octadecadienamide,N-vanillyl-(E,E)-10,13-nonadecadienamide,N-vanillyl-(Z,Z)-11,14-eicosadienamide, andN-vanillyl-(E,E)-11,14-eicosadienamide, and pharmaceutically-acceptablesalts thereof and mixtures thereof.
 15. A composition, according toclaim 10, wherein said alkadienamide compound isN-[(4-acetoxy-3-methoxyphenyl)methyl]-(E,E)-9,12-octadecadienamide. 16.A composition, according to claim 14, wherein said alkadienamidecompound is N-vanillyl-(E,E)-9,12-octadecadienamide.
 17. A method forproducing analgesia in humans or lower animals, which comprisesadministering to said human or lower animal a safe and effective amountof an alkadienamide compound or pharmaceutically-acceptable saltthereof, or mixtures thereof, of the formula: ##STR8## wherein X is 0 orS; R is straight or branched diene having from 11 to 23 carbon atoms; R₁is H, OH, or OCH₃ ; R₂ is OH, or a short-chain ester; and wherein atleast one of R₁ and R₂ is OH or OCH₃.
 18. A method, according to claim17 wherein R of said alkadienamide compound is straight or brancheddiene having from 16 to 21 carbon atoms.
 19. A method, according toclaim 18 wherein said alkadienamide compound is selected from the groupconsisting of N-vanillyl-(Z,Z)-9,12-octadecadienamide,N-vanillyl-(Z,E)-9,12-octadecadienamide,N-vanillyl-(E,E)-9,12-octadecadienamide,N-vanillyl-(Z,E)-9,11-octadecadienamide,N-vanillyl-(E,E)-10,13-nonadecadienamide,N-vanillyl-(Z,Z)-11,14-eicosadienamide,N-vanillyl-(E,E)-11,14-eicosadienamide,N-[(4-acetoxy-3-methoxyphenyl)methyl]-(E,E)-9,12-octadecadienamide, andpharmaceutically-acceptable salts thereof and mixtures thereof.
 20. Amethod, according to claim 18, wherein said alkadienamide isadministered intramuscularly.
 21. A method, according to claim 18, forproducing analgesia in humans or lower animals, wherein saidalkadienamide is administered orally.
 22. A method, according to claim18, for producing analgesia in humans or lower animals, wherein saidalkadienamide is administered topically.